Prader-Willi syndrome is a rare genetic disease (PWS; OMIM 176270). PW patients present a complex and progressive phenotype with mainly two phases. From birth until 2-3 years old, patients present feeding impairment with poor suckling and failure to thrive, a severe hypotonia, which tends later to disappear. Paradoxally, from this period they develop hyperphagic obesity. Patients also present many other symptoms such as respiratory distress, growth retardation due to growth hormone deficiency, hypogonadism, sleep disturbances, cognitive difficulties, skin picking, high pain threshold (Bittel and Butler 2005; Muscatelli 2008; Cassidy and Driscoll 2009) behavioural problems and psychiatric troubles probably related with social dysfunctions.
To date, no comprehensive pathophysiological mechanisms have clearly been identified, however much of the phenotype of PWS, including feeding problems, may be consistent with a hypothalamic defect (Swaab 1997). Human studies have mainly focused on hormone and neuropeptide dysregulation that might contribute to the phenotype in adult PW patients, but these dosages have been performed on plasma issued from patients and controls. In parallel, few studies have been reported on histological analysis from Prader-Willi patients'hypothalamus.
Genetically PWS results from the lack of expression of at least two imprinted genes located in the 15q11-q13 region, the paternal copy of these genes being expressed and their maternal copy being always silenced. It is accepted that PWS is a multigenic syndrome, involving more than one mutated gene (Goldstone 2004). From human genetic studies it has been proposed a role of SNORD116 (encoding for Small Nucleolar Orphan RNAs), in the hyperphagia, obesity and hypogonadism described in PWS (Sahoo, del Gaudio et al. 2008; de Smith, Purmann et al. 2009).
MAGEL2 is one of the candidate genes involved in Prader-Willi syndrome. Importantly, the mouse 7C chromosomal region has conserved synteny with the human 15q11-q13 region. Nearly all the content of genes is conserved, their order and their imprinted regulation. By creating and analysing a mouse model mutant deficient for Magel2, the inventors have shown that a Magel2-deficient mouse had an altered onset of suckling activity and subsequent impaired feeding, recalling the feeding phenotype seen in PW newborns. The hypothalamus of Magel2 mutant neonates showed a significant reduction of oxytocin content. Consistently, injection of a specific oxytocin receptor antagonist in wild type neonates recapitulated the feeding deficiency seen in Magel2 mutants. Importantly, a single injection of oxytocin, three to five hours after birth, rescued the phenotype of Magel2 mutant pups, allowing all of them to feed normally and to survive. Thus, this study revealed a role of Magel2 and an unexpected role of OT, via the OT receptor, in the initiation of feeding behaviour just after birth. Importantly, the lethal phenotype and the feeding behaviour deficiency observed in Magel2 KO, were rescued following an injection of 2 μg oxytocin, 3to 5 hours after birth.
In parallel, the inventors showed that adult patients with PWS receiving a single intranasal administration of oxytocin have significantly less disruptive behavior, fewer conflicts and a strong tendency toward less sadness and less appetite.